STATEMENT OF NEED

The overall goal is to update the healthcare professional’s knowledge of cancer detection and prevention and to understand current and new research regarding state-of-the-art care for those with or at risk for cancer.

TARGET AUDIENCE

Intended for advanced practice nurses, registered nurses, and other healthcare professionals who care for cancer patients.

OVERALL EDUCATIONAL OBJECTIVES

Upon completion, participants should be able to:

• Describe new preventive options and treatments for cancer patients
• Identify options for individualizing the treatment for cancer patients
• Review new evidence to facilitate survivorship and supportive care for cancer patients

ACCREDITATION STATEMENT

Dannemiller is approved by the California Board of Registered Nursing, Provider Number 4229, for 1.0 contact hour. RNs outside California must verify with their licensing agency for approval of this course.

DISCLOSURES

The planners and authors of this CE activity have disclosed no relevant financial relationships with any commercial companies pertaining to this activity.

METHOD OF PARTICIPATION

• Read the articles in this section in its entirety.
• Go to www.dannemiller.com/onn-jul-aug-2013
• Complete and submit the CE posttest and activity evaluation.
• Print your Certificate of Credit.

This activity is provided free of charge to participants.

Highlights From the Year's Largest Oncology Conference, Featuring Peer Perspectives From Oncology Nurses

More than 25,000 oncology professionals representing a broad range of specialties attended the 49th Annual Meeting of the American Society of Clinical Oncology, held May 31-June 4, 2013 in Chicago, Illinois. With a theme of “Building Bridges to Conquer Cancer,” experts presented the latest cutting-edge, multidisciplinary developments in oncology care. In this month’s continuing education activity, oncology nurses comment on the practice implications of some of the noteworthy research presented at the meeting.

Breast Cancer

Optimal Paclitaxel Schedule Identified

for Early-Stage Breast Cancer

By Ben Leach

Low-dose weekly paclitaxel is as effective as and has fewer side effects than the standard biweekly schedule for patients with early-stage breast cancer, according to the results of a phase III study presented at the 2013 ASCO Annual Meeting. Abstract CRA1008.

Paclitaxel is typically prescribed in either weekly or biweekly regimens. This is the first study to formally compare the two dosing schedules. The low-dose weekly administration of the chemotherapy agent paclitaxel resulted in equal disease-free survival (DFS) in patients with early-stage breast cancer when compared with biweekly administration of the drug, and although each dosing regimen resulted in a different set of side effects, the weekly dosing schedule appeared to offer a slightly more favorable side-effect profile.

“It’s important to give these drugs in an optimal way,” said G. Thomas Budd, MD, a medical oncologist at the Cleveland Clinic in Cleveland, Ohio, and lead author of the study. Budd noted that paclitaxel used to be given in higher doses every 3 weeks in the treatment of breast cancer until studies showed that the weekly and biweekly schedules in this study yielded superior results.

In this phase III trial, 3294 patients with node-positive or high-risk node-negative operable breast cancer first received treatment with one of three different regimens of doxorubicin and cyclophosphamide, after which they were randomized to receive either a low-dose regimen of paclitaxel weekly for 12 weeks or a standard-dose regimen of paclitaxel every 2 weeks for 12 weeks with pegfilgrastim support.

As of April 2013, DFS was essentially the same with both schedules of paclitaxel (hazard ratio = 1.05; 95% CI, 0.89-1.25).

“It appears from these data that either way of giving paclitaxel produces a similar outcome,” Budd said. “An investigator and a patient or a doctor and a patient could choose either one of these schedules.”

The rate of any grade 3/4 toxicity was similar across the two arms, occurring in 36% of patients receiving the biweekly regimen and 35% of patients receiving the weekly regimen. However, researchers found that the different dosing schedules were characterized by different types of side effects of different severities. Allergic reactions were more common in the biweekly dose (1.4%) compared with the lower dose (0.6%), as were symptoms of bone and muscle pain (11% vs 3%, respectively).

Neurologic toxicity was also more frequent in the biweekly dose of paclitaxel compared with the low-dose regimen (17% vs 10%, respectively), but Budd noted that patients received six cycles of the biweekly regimen instead of the standard four cycles for the purposes of scientific comparison, which may have slightly affected the frequency of these side effects.

The rate of hematologic toxicity was higher in the weekly-dose arm (17%) than the biweekly-dose arm (6%), as was the rate of leukopenia (6% vs 1%, respectively) and neutrophils (11% vs 2%, respectively). However, the rate of neutropenic fever was low in both groups (0.4% vs 0.1%, respectively) and the difference was not statistically significant (P = .29). Budd explained that the higher rates of hematologic toxicity in the weekly schedule could have been a result of ascertainment bias, since patients had toxicities measured on a weekly basis rather than the biweekly basis of the other study arm.

“In this study, the weekly schedule seemed to be less toxic for most patients,” Budd said.

Axillary Radiotherapy

In Early Breast Cancer

Women with early sentinel lymph nodepositive breast cancer achieve as much of a disease-free and survival benefit from axillary radiotherapy (ART) as they do from axillary lymph node dissection (ALND) with significantly less risk of lymphedema, according to clinical trial results presented at the American Society of Clinical Oncology (ASCO) Annual Meeting. Abstract LBA1001

The findings of the phase III AMAROS trial align with the gradual move away from reliance upon surgery in managing early breast cancer and are likely to be embraced in the United States by patients and oncologists alike, research leaders said in discussing the data.

Andrew D. Seidman, MD, an attending physician for the Breast Cancer Medicine Service at Memorial Sloan- Kettering Cancer Center in New York, said the study would influence treatment for women with early breast cancer, a group that makes up approximately 80% of the 230,000 new cases diagnosed in the United States annually. “This is going to represent a new option for patients, other than having full clearance of their axillary lymph nodes,” said Seidman, who served as an ASCO commentator on the study.

Nurse Perspective on Paclitaxel

A. Nicole Spray, APRNHays Med Breast Care CenterHays, KS

The study comparing the dosing schedules of weekly or biweekly administration of paclitaxel for early-stage breast cancer patients is very exciting. Results of this study show that the weekly dosing and biweekly dosing of paclitaxel are both effective and resulted in equal disease-free survival in patients with early-stage breast cancer.

For an oncologist and patient, this study is helpful in determining what regimen option is going to be best for the patient, while not having to compromise the efficacy of this drug. For instance, where we practice in rural western Kansas, many patients find the distance traveled for treatment to be a barrier— be it cost, or travel time, etc. Some patients with early-stage breast cancer can afford the slight increased toxicity of paclitaxel so that they only have to travel every other week.

On the other hand, it is helpful to know that some women may not be able to tolerate the larger biweekly dose of paclitaxel but may benefit and tolerate the once-weekly administration of this drug. For these patients, the only other option would have been to not administer paclitaxel at all due to concern over adverse side effects and tolerability. Either way of administering paclitaxel gives the patient and treating oncologist options for efficacious treatment that does not compromise chance of cure.

BOLERO-3: Everolimus Might Help Patients

Overcome Trastuzumab Resistance

Adding the mTOR inhibitor everolimus to conventional therapy slowed the progression of trastuzumab-resistant advanced breast cancer, and in the process, provided clues to the origin of trastuzumab resistance. The findings came from the results of the phase III BOLERO-3 trial, which were presented at the 2013 ASCO Annual Meeting. Abstract 505

In the study, patients treated with everolimus (Afinitor) in addition to trastuzumab (Herceptin) and vinorelbine had a median progression-free survival (PFS) of 7 months compared with 5.78 months in patients who received trastuzumab, vinorelbine, and a placebo.

A preliminary analysis of overall survival (OS) suggested an advantage for everolimus-treated patients, but a final determination will require longer follow-up.

“This is the first phase III study showing a benefit of mTOR pathway inhibition in HER2-positive breast cancer,” said Ruth O’Regan, MD, associate professor of Medicine at Emory University in Atlanta, Georgia, who reported the findings at the ASCO meeting. “Targeting the mTOR pathway is a viable approach to maximize the benefit of trastuzumab-based therapy.

“The combination of everolimus plus vinorelbine plus trastuzumab may be considered an appropriate option in trastuzumab-resistant HER2-positive advanced breast cancer,” O’Regan said.

Although trastuzumab has significantly improved outcomes for patients with HER2-positive breast cancer, patients who develop metastatic disease almost inevitably have trastuzumab resistance. The mechanisms by which resistance occurs remain unknown, but include the possibility of activation of the mTOR pathway, which everolimus targets.

Two small, phase Ib trials demonstrated everolimus activity in trastuzumab-resistant HER2- positive breast cancer, supporting the hypothesis that inhibiting the mTOR pathway might reverse trastuzumab resistance, said O’Regan.

Everolimus has FDA approval for use in HER2- negative breast cancer but remains investigational in HER2-positive disease.

The international BOLERO-3 trial involved 572 women with locally advanced or metastatic HER2- positive breast cancer. All of the patients had progressed during or after treatment with trastuzumab and a taxane.

Investigators in six countries randomized patients to the trastuzumab-vinorelbine combination with or without everolimus. Treatment continued until progression or development of unacceptable toxicity. The trial had a primary endpoint of PFS, and secondary outcomes included OS, overall response rate, and time to deterioration of performance status.

About half of the patients had received trastuzumab for a year or more and half for less than a year. All of the patients had received a taxane in addition to trastuzumab. A quarter of the patients in each group had a treatment history that included the anti-HER2 agent lapatinib (Tykerb). The median time from the last trastuzumab treatment to randomization was 1.4 months. More than 40% of patients had received two or more prior regimens.

Treatment continued for 24 weeks in both arms. The >1-month difference in median PFS translated into a hazard ratio of 0.78 in favor of everolimus (P = .0067). An extensive subgroup analysis showed a consistent benefit for the addition of everolimus, regardless of age, prior lapatinib therapy, nature and duration of prior trastuzumab therapy, performance status, hormone-receptor status, or visceral involvement. O’Regan noted that patients aged <65 years and those who had received prior trastuzumab early in the course of treatment seemed to derive greater benefit from everolimus.

Data have not matured sufficiently for an analysis of OS. Nonetheless, the preliminary results showed lower mortality in the everolimus group (36.3% vs 41.1%).

The treatment arms had similar response rates of 41% with everolimus and 37.2% with placebo. Additionally, 48.2% of the everolimus group had stable disease compared with 41.4% of the placebo group. Neither difference reached statistical significance.

Adverse events occurred more frequently in the everolimus group. The most common events associated with everolimus (all grades) were stomatitis (63%), fatigue (43%), pyrexia (39%), diarrhea (38%), nausea (35%), decreased appetite (33%), constipation (30%), and rash (25%). Grade 3 events were infrequent and grade 4 events rare.

The addition of everolimus did not adversely affect quality of life, as indicated by the similarity of time to deterioration of performance status in both groups, said O’Regan.

Nurse Perspective on BOLERO-3:

Janice Famorca Tran, RN, MS, AOCNP®, CBCN®, ANP-CTexas OncologyHouston, TX

Previous breast cancer studies have demonstrated the benefit of everolimus in hormone-positive, HER2-negative advanced breast cancer; however, the recent phase III BOLERO-3 trial revealed the clinical benefit of everolimus in hormone-positive, HER2-positive breast cancer as well.

In advanced breast cancers, there is eventual resistance to trastuzumab, and the activation of the mTOR pathway has been identified as a culprit in this resistance.With the addition of the mTOR inhibitor everolimus to trastuzumab, progression of the disease is slowed.

Due to the potential side effects of everolimus, including stomatitis, diarrhea, anemia, and rash, with more serious side effects such as pneumonitis, nurses must be judicious in their assessment of their patients receiving this drug. More importantly, proactive management of these symptoms is essential so that patients can continue taking the drug without experiencing intolerable side effects. Patients and their family members should be educated on these side effects, so that they, too, can take an active role in management of symptoms.

Treatment for breast cancer has made innovative strides over the last several years. As we identify the pathways that drive the tumor, treatment for this disease becomes much more specific and targeted. With each new stride in breast cancer, we become closer to hopefully finding a cure for this disease. The BOLERO-3 treatment regimen offers an additional promising option for this subset of breast cancer patients.

Gynecologic Cancer

Pazopanib Maintenance Therapy Delays Relapse of Advanced Ovarian Cancer

By Beth Fand Incollingo

An oral targeted drug already approved by the FDA for the treatment of kidney cancer and soft tissue sarcoma has been found to extend disease-free survival in women with advanced ovarian cancer, according to study results presented at the 2013 ASCO Annual Meeting. Abstract LBA5503

The phase III, randomized, multicenter clinical trial (AGO-OVAR16) showed that pazopanib (Votrient), following initial successful chemotherapy, extended disease-free survival by an average of 5.6 months compared with a placebo in patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (AEOC).

The goal of treatment with pazopanib would be to maintain the successful but typically short-lived response experienced by these patients after initial treatment, said the study’s lead author, Andreas du Bois, MD, PhD, a professor of Gynecologic Oncology at Kliniken Essen Mitte in Essen, Germany. Since there is no test available to predict a patient’s risk for relapse, a maintenance therapy such as this one would be used for most patients in this population, experts at the ASCO meeting noted.

If approved in this setting, pazopanib would be the first maintenance therapy for the treatment of ovarian cancer in the United States, although bevacizumab (Avastin) is registered for use concurrently with chemotherapy and subsequently as maintenance therapy in Europe.

“Our findings show that we finally have a drug that can maintain control over ovarian cancer growth achieved through initial treatments,” du Bois said. “If pazopanib is approved for ovarian cancer, many patients will experience longer disease-free and chemotherapy-free periods. During this time, the patient keeps control over the disease instead of the disease having control over the patient’s life.”

Pazopanib is an oral, multikinase inhibitor that blocks several targets involved in tumor angiogenesis, which “plays a major role” in AEOC, du Bois said.

Ovarian cancer is the fifth leading cause of cancer death among women in developed countries, and has the highest mortality risk among all gynecologic tumors. At the time of diagnosis, 70% of patients already have advanced disease, which is associated with a cure rate of only 20%-25%, according to ASCO.

While 70% to 85% of patients are free of their tumors after initial treatment with surgery and chemotherapy, three-quarters of them experience recurrences, and half of those recurrences take place within the first year, du Bois said. Such patients typically live 2 to 4 years from the time of diagnosis, and can receive up to five lines of treatment during the course of their disease, he said.

The study was designed to evaluate the efficacy, safety, and tolerability of pazopanib maintenance therapy in patients who had not progressed after first-line platinum-taxane chemotherapy for AEOC, with a primary endpoint of progression-free survival (PFS). Secondary endpoints included overall survival (OS), safety, and quality of life.

In the study, 940 patients, most of whom (91%) had stage III/IV AEOC, were randomized 1:1 to receive either pazopanib or placebo daily for 24 months. All patients had prior surgery and five or more rounds of chemotherapy that prevented the disease from worsening.

Patients in the pazopanib arm had a prolonged PFS vs placebo (17.9 vs 12.3 months, respectively). The first interim analysis for OS (189 patients) showed no difference between arms, but those data will not be considered mature until it includes 551 events, du Bois noted.

As compared with a placebo, pazopanib treatment was associated with a higher incidence of adverse events (AEs) and serious AEs (26% vs 11%), several of them class-specific, including elevated liver enzymes. The most common were hypertension, diarrhea, nausea, headache, fatigue, and neutropenia, du Bois said. Fatal AEs were reported in three patients on pazopanib and one patient on placebo.

An immediate goal for this research is to combine pazopanib with other targeted drugs and personalize therapy according to patient and tumor characteristics, ASCO stated.

Nurse Perspective on Ovarian Cancer

Emily Beard, RN, OCN, CBCNMultidisciplinary Care CoordinatorOncology Support ServicesNorthside Hospital Cancer InstituteAtlanta, GA

For those of us who sit in multidisciplinary tumor boards every week and discuss the all-too-predictable course of advanced ovarian cancer, we know the vast majority of these patients—no matter how optimal their surgery and response to chemotherapy is initially&mdash;will develop a recurrence. Since it is such a challenging and unpredictable diagnosis with considerably limited treatment options, the idea of a proven maintenance drug for advanced ovarian cancer is very exciting.

However, the optimism also comes with a lot of implications for oncology nurses to consider in managing patients on this therapy. The challenges related to oral therapy adherence are well documented: Patients are less likely to take medications when they are given in pill form. Oncology nurses have a knack for developing rapport with patients and caregivers, and never has it been more important to ensure consistent dose-scheduling, symptom education, and reinforcement of this information. Nurses must become expertly knowledgeable regarding drug-specific symptom management and be on high alert for adverse events, such as severe diarrhea and hepatotoxicity. It often falls on clinic nurses to address quality-of-life issues—when is enough, enough&mdash;for a fragile population of patients already battered by multiple rounds of first-line chemotherapy.

While there is still much to study and understand about the role of pazopanib (and potentially other multikinase inhibitors) in the treatment of advanced ovarian cancers, these results represent a critical step forward. For individual patients and clinicians who are already doing everything they can to keep at bay the threat of recurrent cancer, this research represents a ray of hope. The average 5.6 month extension of disease-free survival may seem small and insignificant in the context of a lifetime, but it is all about timing.

Knowing that there are multiple agents being developed and tested in labs all over the world, the best that research can deliver patients and clinicians now—short of a durable cure&mdash;is time and options.

Melanoma

Combining Ipilimumab and Nivolumab Shows Promise

in Advanced Melanoma

By Jason M. Broderick

Combining the checkpoint antibodies ipilimumab (Yervoy) and nivolumab (formerly BMS-936558) led to deep tumor regression in approximately one-third of patients with advanced melanoma in an ongoing phase I study. Additionally, responses to the combination were quicker than those normally observed with immunotherapy. Abstract 9012

“The activity [in this study] appeared to be distinct from published data for nivolumab and ipilimumab monotherapy,” said Jedd D. Wolchok, MD, PhD, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York City, who presented the research.

Ipilimumab was approved by the FDA in 2011 for metastatic melanoma, and clinical research has shown strong response rates for nivolumab in patients with the disease.

The two antibodies have similar mechanisms of action, in that they “both block pathways that are essentially molecular brakes which prevent T cells in the immune system from achieving a full and persistent state of activation,” said Wolchok.

Specifically, ipilimumab and nivolumab block the inhibitory checkpoints CTLA-4 and PD-1, respectively. “By blocking these braking pathways, [the two treatments] each result in immune activation in different ways,” said Wolchok.

The combination study was launched after preclinical animal studies demonstrated that using the treatments together proved more effective than monotherapy with either drug. In the trial, patients with nonresectable stage III or IV metastatic melanoma previously treated with three or fewer therapies were assigned to one of six treatment arms.

There were four concurrent and two sequenced cohorts. In the concurrent arms, patients received four doses of nivolumab (0.3-3 mg/kg) and ipilimumab (1-3 mg/kg) every 3 weeks, followed by nivolumab alone every 3 weeks for four doses. Every 3 months, there was one combination treatment administered at week 24. In the sequenced cohorts, patients previously treated with ipilimumab outside of the study received nivolumab alone (1 or 3 mg/kg) every 2 weeks.

When data from the concurrent cohorts were combined, “Forty percent [of patients] had objective responses. If one broadens this to include patients who had slow responses, or stable findings on scans, then 65% of patients had the melanoma controlled with this combination. Ninety percent of the responding patients continued to respond as of February 2013,” said Wolchok.

In the largest concurrent group, patients received the FDA-approved dose of ipilimumab (3 mg/kg), along with 1 mg/kg of nivolumab (n = 17). In this cohort, the objective response rate (ORR) was 53% (95% CI, 28-77) and 41% of patients (n = 7) had ≥80% tumor reduction at week 12.

With patients in the largest sequenced cohort (n = 16), the ORR was 38% (95% CI, 15-65) and four patients had tumor reduction ≥80%.

Regarding the sequenced cohort results, Wolchok said, “The important [point] here is that there were responses noted. Even in patients who previously showed growth or progression of disease on ipilimumab. This indicates that even when one immunotherapy does not provide a response, patients can still respond to another immune modulator. This further supports the importance of studying combination therapy with medicines targeting distinct pathways.”

Toxicities with both the concurrent and the sequenced cohorts were manageable and generally reversible using protocols previously developed to address the side effects of each treatment individually.

Grade 3/4 side effects occurred in 53% of patients receiving concurrent treatment and 18% of patients in the sequenced cohorts. Elevation of liver or pancreatic enzymes were the most common side effects for both treatments. There have been no treatment-related deaths in the study.

Based on the results, a randomized phase III trial of the ipilimumab/nivolumab combination versus nivolumab alone versus ipilimumab alone in advanced melanoma is scheduled to start this year.

Nurse Perspective on Immunotherapy

Rajni Kannan, BS, MS, RN, ANP-BCNurse PractitionerNYU Cancer InstituteNYU Langone Medical CenterNew York, NY

Immunotherapy in melanoma patients has significantly changed treatment options and survival. This study focuses on the combination of two immunotherapies that together increase response rates significantly. Not only did the study show that the combination of ipilimumab and nivolumab increases response rates, the study also shows that patients who have progressed on one immunotherapy may still respond to subsequent treatments with other immunotherapy treatments. This is a new observation, for it was previously assumed that if a patient progressed on one immunotherapy, they were unlikely to respond to another. This increases the therapies available to metastatic melanoma patients.

The side-effect profiles of the two agents are similar in causing autoimmune-like side effects, such as colitis, hepatitis, and dermatitis. It is important to note that there are an increased number of occurrences of pneumonitis seen with nivolumab alone and when used in combination with ipilimumab. This is an important side effect of nivolumab that oncology nurses should be aware of so it is diagnosed at the early onset of symptoms.

Combination therapy targeting particular pathways is the future in metastatic cancer. We are learning more through research studies such as these that combination therapy has a significant role in the treatment of patients with metastatic cancer.

Five years ago it was difficult to talk about survival in melanoma patients. Chemotherapy had a very low response rate. But now with studies such as this combination trial of ipilimumab and nivolumab we are seeing response rates of 40%. Five years ago melanoma survivorship was not a focus, but with new immunotherapies, biotherapies, and combination therapies melanoma survivorship is a topic oncology nurses are focusing on. We will continue to see significant progress in the treatment of metastatic melanoma and progress in the response rates to new and combination therapies.

Prostate Cancer

Advances in Prostate Cancer Treatment

and Supportive Care

Highlights from 2013 ASCO include the following three abstracts on prostate cancer treatment and supportive care.

Fewer Side Effects With Enzalutamide Monotherapy

In a phase II study in patients with hormone-naïve prostate cancer, the oral androgen receptor (AR) inhibitor enzalutamide achieved a “high response rate and marked PSA decline,” with efficacy similar to castration but without the side effects of androgen-deprivation therapy. During the 6-month, single-arm trial, bone mineral density remained stable, and metabolic variables, such as fat body mass, lipid profiles, and glycemic profiles did not show substantial changes.

The researchers assessed enzalutamide monotherapy at the approved dose of 160 mg per day for 25 weeks in patients with hormone-naïve prostate cancer and noncastrate testosterone ≥230 ng/dL (N = 67). The primary endpoint was PSA response, defined as ≥80% decline at the study’s end.

“We know that a lot of patients will need androgen- deprivation therapy,” said principal investigator Bertrand Tombal, MD, PhD, professor and chairman, Department of Urology, Cliniques Universitaires Saint-Luc, Brussels, Belgium. “In Europe, we have been using androgen monotherapy…and these drugs have the ability to control the cancer without requiring androgen-deprivation therapy.” The goal is to develop an alternative to standard hormone therapy.

“We took a really conservative approach in these patients…showing a PSA drop of more than 80%, to be sure, at least, that if it didn’t reach that endpoint, we would know that we couldn’t go further. In fact, it did much better than that, depressing PSA very, very profoundly. Asked about a key message for clinicians today, Tombal said, “Look at these drugs and try to think outside the box of standard hormonal therapy.” Abstract 5001

Radium-223 Reduces Pain and Opioid Use

The FDA approved radium 223 dichloride (radium- 223; Xofigo) in May for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases, and no known visceral metastatic disease. The decision was based on results from the phase III ALSYMPCA study. A post hoc pain analysis of ALSYMPCA reported at ASCO 2013 by Sten Nilsson, MD, PhD, from the University of Oslo, Norway, found that in addition to prolonging survival, radium-223 reduced pain and opioid use in patients with CRPC and bone metastases.

Radium-223 is an alpha-particle emitting radiotherapeutic drug that mimics calcium and forms complexes with hydroxyapatite at areas of increased bone turnover, such as bone metastases. In ALSYMPCA, patients with CRPC with bone metastases were randomized 2:1 to six injections of radium-223 (n = 614) or placebo (n = 307).

The Cox proportional hazards model was used by Nilsson et al for an analysis of time to initial opioid use and time to external-beam radiation therapy. Pain-related quality of life (QoL) was analyzed using the Functional Assessment of Cancer Therapy- Prostate subscale, using ANCOVA.

At baseline, approximately 55% of ALSYMPCA patients had moderate-to-severe pain and opioid use, based on the World Health Organization ladder for cancer pain.

The median time to opioid use was significantly longer in the radium-223 group, with a risk reduction of 38% versus placebo. Fewer patients who received radium-223 required opioids for pain relief than placebo-treated patients (36% vs 50%, respectively). And at week 16, the QoL pain score reflected significant reductions in pain among the radium-223 group (P =.001). Abstract 5038

Additional COU-AA-302 Abiraterone Acetate Data

The international COU-AA-302 trial assessed the clinical benefit of abiraterone acetate (AA) plus prednisone in 1088 chemotherapy-naïve mildly symptomatic or asymptomatic patients with progressive mCRPC. The study was the basis for the FDA’s decision in December to expand the indication of AA to the prechemotherapy setting for mCRPC.

In the final report on the long-term safety and efficacy analysis of COU-AA-302 presented at ASCO, lead author Dana E. Rathkopf, MD, Memorial Sloan-Kettering Cancer Center, New York City, said that at a median follow-up of 27.1 months, radiographic progression-free survival was significantly improved in patients receiving AA. However, although overall survival was improved with AA over prednisone, it did not reach the prespecified efficacy boundary.

Co-investigator Neal D. Shore, MD, medical director of Carolina Urology Research Center in Myrtle Beach, South Carolina, commenting on these data, said, “We saw absolutely no new differences in safety signals or in toxicity parameters. But what we did see was a continued significant trend in survival. Although it did not meet a prespecified boundary, [there was] an obvious trend with a P value of .015. More important was the improvement in radiographic progression-free survival—almost a doubling from 8 months to 16 months in the treatment arm.” Abstract 5009

Nurse Perspective on mCRPC

Frank delaRama, RN, MS, AOCNSClinical Nurse Specialist, Oncology/GenomicsProstate Cancer Nurse NavigatorPalo Alto Medical FoundationPalo Alto, CA

Helping our patients deal with locally advanced and metastatic prostate cancer can quickly become a complex process, given the variety of regimens involving chemotherapy, immunotherapy, radiotherapy, and hormone therapy. Emerging technologies, as recently presented at ASCO, add yet more options to the mix, further challenging both healthcare providers and their patients in making treatment decisions.

Enzalutamide shows some early promise as single-agent antiandrogen therapy in the research from Smith and colleagues. A standard regimen that includes bicalutamide and a luteinizing hormone—releasing hormone (LHRH) antagonist proves to be effective in PSA response; castrate levels of testosterone can have worrisome effects on bone density, fat body mass, lipid, and glycemic profiles.

Used in the absence of LHRH agents, enzalutamide exhibits an effective PSA response while maintaining bone density and the metabolic variables of concern. With only 6 months of data, further research should focus upon the long-term effects of this novel agent. Another concern would be whether or not treatment with enzalutamide would reduce the efficacy of subsequent treatments, chemotherapy, radiotherapy, or even more hormonal therapy.

As a CYP17 inhibitor, abiraterone works to disrupt the pathway in the body’s manufacturing of testosterone. Rathkopf et al presented some long-term data that support safety and efficacy in chemo-naïve patients receiving this oral agent. The data showed efficacy in several measures, including time to radiographic progression, to opiate use, and also to chemotherapy use. Timing of treatments seems to be a key point of the study, further supporting first-line therapy with abiraterone, to optimize progression-free survival.

Finally, with the new availability of Radium-223, we have a radiotherapeutic agent to help improve quality of life in our patients with symptomatic bone metastases from hormone-resistant prostate cancer. The data demonstrated efficacy through increasing time to external-beam radiotherapy, and to initial opioid use. Quality-of-life pain scores were reduced at the 16-week point.

Prostate cancer that has become locally advanced or even metastatic often refocuses the attention of all involved (patients, families, and even healthcare providers) to quality-of-life issues. This becomes priority number one. Developing therapeutic agents, such as the three reviewed here, can have great impact on quality of life, as evidenced by the data presented. As caregivers, we can foster our patients’ quality of life by sharing our knowledge of the opportunities, as well as the challenges, related to these novel treatments.

Head and Neck Cancer

Partners of HPV-Positive Oropharyngeal Cancer Patients Not

at Increased Risk of HPV Infection or Oral Cancer

By Lauren M. Green

Patients with human papillomavirus— positive oropharyngeal cancer (HPV-OPC) and their spouses may find some reassurance in a recent study by researchers at the Johns Hopkins Bloomberg School of Health. The study found that partners are no more likely to be infected by HPV than the general population, and their risk of contracting HPV-OPC remains low. Abstract CRA6031

Findings of this pilot study—the first large study to examine oral HPV infection among patients with HPV-OPC and their partners&mdash;were announced at the 2013 ASCO Annual Meeting.

The majority of oropharyngeal cancers in the US are now caused by HPV, and the incidence of HPVrelated oropharyngeal cancer is increasing significantly, noted the study’s lead author, Gypsyamber D’Souza, PhD, MPH, MS, associate professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. “Some of the patients with this diagnosis worry about oral HPV transmission and the cancer risk to their partners or spouses.”

To better understand this possible increased risk, D’Souza and colleagues enrolled a total of 166 patients with HPV-OPC; 94 of them had spouses or long-term partners who were also enrolled in the study. DNA samples were collected from both groups, following administration of a 30-second mouth rinse and gargle. Samples were obtained at the time of diagnosis and 1 year later.

Median age of the HPV-OPC patients was 56 years; 89% were male, 92% were white, non-Hispanic, and 94% had performed oral sex. Their partners were predominantly female (94%) and white, non- Hispanic (92%), with a median age of 53 years. Patients were significantly more likely to have had >10 oral sex partners over their lifetime (39%), versus their spouses/partners (11%).

Samples were analyzed for the presence of 36 subtypes of HPV DNA, among them, the most prevalent type found in the majority of HPV-OPC cancers—HPV16. DNA is considered the “gold standard” for determining presence of HPV in the tumor, D’Souza explained.

She noted that for individuals without cancer, examining exfoliated oral cells from the rinse/gargle samples is the best available option for measuring oral HPV infection, since there is currently no validated, FDA-approved test.

Researchers found that nearly two-thirds of the cases (65%) had HPV DNA in their oral exfoliated cells, and a little over half (54%) of these cases had HPV16, said D’Souza. After 1 year and completion of treatment, analysis of the oral rinse samples from the HPV-OPC cases demonstrated that a “vast majority of these cases no longer had any HPV16 DNA detectable,” she added.

The prevalence of HPV among the long-term female partners of patients was 5%, which is comparable to the 4% prevalence among women in the general population, based on previously published data. HPV16 was found in just 2.3% of female partners and in none of the small number of male partners. In addition, no pre-cancers or cancers were detected in the 60 partners/spouses who underwent a visual oral exam.

“These findings provide assurance that prevalence of oral HPV infection is not increased among partners [of patients with HPV-OPC], and their risk of HPV-OPC remains low,” said D’Souza. “Couples who have been together for several years have likely shared whatever infections they have, and no changes in their physical intimacy are needed.”

D’Souza concluded her presentation by noting that while oral HPV infection remains common, “many individuals who become infected are able to clear these infections and not get cancer.”

“HPV is responsible for thousands of cases of cancer of the oropharynx, cervix, and other sites every year,” noted Gregory Masters, MD, ASCO spokesperson and moderator of the press briefing where the results were announced.

“This study improves our understanding of HPV risk among the partners of patients with HPVpositive oropharyngeal cancers. I’m sure this news will provide long-awaited reassurance for patients, as well as their spouses and partners.”

Oncology Practice

Web-Based Patient Education Tool Reduces

Barriers to Clinical Trial Participation

By Lauren M. Green

A large-scale, randomized, multicenter phase III trial testing the effectiveness of a tailored, interactive, Web-based video intervention has demonstrated that educational information delivered online prior to meeting with an oncologist can significantly reduce barriers to patient participation in clinical trials. Abstract 6500

Although clinical trials are critical for improving cancer care, only a small percentage of patients participate in them. The online tool, known as PREACT (Preparatory Education About Clinical Trials), was developed to test whether assessing and addressing the patient’s attitudinal and knowledge barriers before the oncologist visit, would better prepare patients to consider clinical trials as an option for their cancer treatment.

Neal Meropol, MD, division chief, Hematology and Oncology, at University Hospitals Case Medical Center in Cleveland, Ohio, presented the trial’s findings at the 2013 ASCO Annual Meeting on behalf of the PRE-ACT study group, which is made up of representatives from several leading cancer centers and patient advocacy organizations.

For the study, adult cancer patients (median age = 59; range, 20-88) served by one of four National Cancer Institute (NCI)—designated cancer centers, completed an online questionnaire to obtain a baseline understanding of their attitudes (Box) and knowledge about clinical trials, as well as gauge their preparation and preferences for decisionmaking and quality of life. The most common tumor types in the patient sample were breast, lung, colorectal, prostate, and pancreatic.

The patients were then randomized to receive either PRE-ACT or a control educational intervention. PRE-ACT involved providing patients with a feedback summary of their barriers and preferences plus short (30-90 seconds) video clips addressing three core topics, as well as their own top clinical trial barriers. The control intervention consisted of general text about clinical trials excerpted from NCI materials. Both groups were given the hyperlink to the NCI clinical trials website.

Examples of PRE-ACT video topics include:

• What are clinical trials?
• Is there a clinical trial for everyone?
• What is randomization?
• Will I get good care if I take part in a clinical trial?
• Will I have side effects on a clinical trial?

Following the interventions, a follow-up online survey assessed clinical trial barriers and preparation for both cohorts. Of the 1255 patients randomized for the trial, 1081 (89%) completed both the baseline and post-intervention assessments, and 733 patients (68%) participated in an assessment after their oncologist visit.

Both groups demonstrated better knowledge and preparation and a reduction in attitudinal barriers to clinical trial participation, but PRE-ACT showed superior efficacy over the control intervention for improving knowledge (P = .0006) and attitudes (P = .0001). Patients in the PRE-ACT group also were more satisfied with the information they received and felt better equipped to make a decision about participating in a clinical trial.

In the area of knowledge, the video interventions had a positive impact overall, and this was true for the majority of videos aimed at addressing attitudinal barriers to clinical trial participation. “Notably,” however, said Meropol, “the two concerns related to the cost of clinical trial participation [‘Insurance Won’t Pay’ and ‘Can’t Afford’] were heightened by the videos.”

Study limitations cited by Meropol included the fact that the effect sizes for control text and PREACT were large for knowledge but modest in the areas of attitudinal barriers and preparation. He added that PRE-ACT requires access to a computer and high-speed internet, and therefore may not be available to all cancer patients.

Meropol said that research is ongoing to identify which patients are most likely to benefit from the PRE-ACT approach and to explore the downstream impact of PRE-ACT versus NCI text on decisional conflict and clinical trial enrollment.

Top 5 Attitudinal Barriers to

Clinical Trial Participation

• Fear of side effects
• Worry that the trial won’t work for them
• Afraid of receiving a “sugar pill” instead of real medicine
• Fear that health insurance won’t pay for the trial
• Not inquiring about clinical trials unless their physician brought the option up first

Nurse Perspective on Clinical Trials

Kristin Barber, RN, MSN, APRNUtah Cancer SpecialistsSalt Lake City, UT

The importance of clinical trial participation is very apparent in oncology. It is vital that we continue to find ways to enroll more patients in trials. Often patients have misconceptions about clinical trials. Identifying these misconceptions and educating patients and their families would likely increase participation. According to ClinicalTrials.gov, as of August 1, 2013, there are 149,923 clinical trials offered in 50 states and 185 countries, and we have been increasing the amount of studies offered each year.

This trial illustrates a practical way we can inform and educate patients about clinical trials. What is compelling about this trial is that both interventions were effective but the 30-90 second video clips were more successful, and patients had higher satisfaction and were better able to make a decision about enrollment. I would like to see this incorporated into all oncology clinics possibly, with the National Cancer Institute providing the clips now that we have evidence to support their utility.

Lung Cancer

In Treating Locally Advanced NSCLC,

More Radiotherapy Is Not Better

By Beth Fand Incollingo

Radiotherapy at a higher-than-standard dosage is harmful to patients with locally advanced non-small cell lung cancer (NSCLC) who are also getting concurrent and consolidation chemotherapy, according to findings of a study reported at the 2013 ASCO Annual Meeting. Abstract 7501

In a phase III trial, patients with stage III NSCLC who were given the standard 60 gray (Gy) dose of radiotherapy lived approximately 9 months longer and experienced fewer treatment-related deaths than those treated with a high dose of 74 Gy. Those who received the high dose faced a 56% greater risk of death and a 37% greater risk of local progression of their disease compared with patients who received the standard dose, according to lead author Jeffrey D. Bradley, MD, a professor of Radiation Oncology at the Washington University School of Medicine in St. Louis, Missouri.

Promising findings in phase I and II trials encouraged some physicians to give high-dose radiation to patients in this population with the expectation of better outcomes, but Bradley said these most recent findings could reverse that trend.

“We expected at the outset that high-dose radiation therapy would lead to better outcomes. We were surprised, though also pleased, to discover that less intense treatment led to better control of cancer progression and spread, and even improved overall survival,” Bradley said.

In the study, 464 patients were randomly assigned to treatment with standard-dose (SD) or high-dose (HD) radiation therapy along with standard chemotherapy (paclitaxel and carboplatin), with a primary endpoint of overall survival. The HD arm was closed after an interim analysis showed it was not superior to the SD arm.

Of the participating patients, 419 were eligible for analysis. The median survival for patients who received SD radiation therapy was much longer compared to that of patients who received HD radiation therapy (28.7 months vs 19.5 months), and the estimated 18-month overall survival rate was also higher for the SD arm (66.9% vs 53.9%). Cancer recurrence rates at 18 months were higher in the HD group of patients compared with the SD group; local recurrence rates were 34.3% versus 25.1%, and distant recurrence rates were 44% versus 35.3%.

Whereas the primary cause of death for most patients was lung cancer (72.2% in the SD arm vs 73.5% in the HD arm), there were a notably higher number of treatment-related deaths in the HD arm (10) as compared with the SD arm (2). Adverse events that were grade ≥3 occurred at a rate of 74.2% versus 78.2% in the SD and HD arms, respectively. Possible explanations for the poorer outcome for patients on the HD arm, Bradley said, include increased exposure of the heart to radiation; the longer duration of therapy in the HD arm (7.5 weeks as compared with 6 weeks in the SD arm); unreported toxicities; or a combination of those factors.

“This is a critical study in the field of radiation oncology,” said ASCO President Sandra M. Swain, MD. “After a decade of research, we can finally close the chapter on the high-dose versus standarddose therapy debate in lung cancer, using evidencebased data to improve care for our patients.”

Kidney Cancer

First-Line Standard for Metastatic RCC Upheld

The standard of care for metastatic renal-cell carcinoma (RCC) prevailed in a randomized comparison of everolimus (Afinitor) and sunitinib (Sutent) as firstline therapy, according to data presented at the 2013 ASCO Annual Meeting. The trial failed to demonstrate the noninferiority of everolimus for progressionfree survival (PFS), as sunitinib-treated patients had a median PFS of nearly 3 months greater than that of patients treated with everolimus. Abstract 4504

Subgroup analysis did not identify any efficacy advantages with everolimus with respect to PFS or overall survival (OS), which was about 8 months longer with sunitinib. “Progression-free survival noninferiority was not achieved for first-line everolimus compared with sunitinib,” said Robert J. Motzer, MD, attending physician in Genitourinary Oncology at Memorial Sloan-Kettering Cancer Center in New York City.

“The sequence of first-line sunitinib followed by everolimus is supported by the preliminary overall survival results,” said Motzer. “The standard treatment paradigm remains first line with sunitinib followed by everolimus at progression.”

Everolimus has approval as a second-line therapy for metastatic RCC following progression on sunitinib. Efficacy in the second line and a favorable safety profile created a rationale to evaluate everolimus as first-line therapy.

Motzer reported findings from a phase II randomized comparison of the two agents in patients with metastatic RCC. Eligible patients had clear-cell or non—clear-cell RCC and no prior systemic therapy. Some patients had received nephrectomies.

Patients were randomized to first-line treatment with everolimus or sunitinib and crossed over to the other drug at disease progression. Second-line therapy continued until disease progression or development of unacceptable toxicity.

Investigators randomized 471 patients to initial therapy with everolimus or sunitinib. Subsequently, 201 patients in the everolimus arm (85%) and 192 in the sunitinib group (82%) discontinued first-line therapy, primarily because of disease progression (55% with everolimus, 52% with sunitinib).

Motzer reported that 207 randomized patients crossed over to second-line therapy. Second-line discontinuation rates were 71% with everolimus and 76% with sunitinib, and progression accounted for a majority of discontinuations.

Assessment of the primary endpoint showed a median PFS of 10.7 months with first-line sunitinib versus 7.85 months with everolimus.. The objective response rate was 8% with everolimus and 26.6% with sunitinib, and disease stabilization occurred in 57.6% and 51.9% of the respective groups. Median OS was 22.4 months with everolimus-sunitinib and 32 months with sunitinib-everolimus.

Treatment-emergent adverse events during first-line therapy occurred in a similar proportion of patients in each arm. The most common adverse events (≥10% of patients, all grades) were stomatitis, fatigue, diarrhea, cough, rash, nausea, decreased appetite, anemia, peripheral edema, dyspnea, dysgeusia, vomiting, constipation, handfoot syndrome (sunitinib), and thrombocytopenia (sunitinib).

Hematologic Malignancies

GA101 Delivers Significant Gain in Pivotal CLL Trial

Obinutuzumab (GA101), a novel antibody that targets CD20, demonstrated a dramatic advantage in response rates when added to chlorambucil compared with the chemotherapy agent alone in elderly patients with chronic lymphocytic leukemia (CLL), investigators reported at the 2013 ASCO Annual Meeting. Abstract 7004

The agent also delivered higher response rates than rituximab (Rituxan) plus chlorambucil did in the same population, although full data comparing the two antibodies in a head-to-head stage of the phase III study are not yet mature.

Overall, the GA101 combination regimen more than doubled median progression-free survival (PFS), the primary endpoint of the trial, to 23.0 months compared with 10.9 months for chlorambucil alone, resulting in an 86% reduction in the risk of progression.

The PFS for the GA101 arm is likely to increase with longer follow-up time, said lead investigator Valentin Goede, MD, of the Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, Germany.

In addition to the results, the CLL11 study is noteworthy because it is the first pivotal trial conducted in a large population of previously untreated older adults with comorbidities typically seen in practice, said Goede.

Elderly patients with CLL have been “heavily underrepresented” in clinical trials even though they make up a majority of patients diagnosed with the disease, Goede noted.

In the international CLL11 study, 780 patients are being randomized to receive chlorambucil; chlorambucil plus GA101; or chlorambucil plus rituximab.

Goede reported PFS results for 118 in the chlorambucil group, 238 patients in the GA101 arm, and 233 participants in the rituximab group. An additional 190 patients will be included in the stage II results.

In stage IA of the 2-stage study at the cutoff time (July 11, 2012), the overall response rate (ORR) among 212 patients in the GA101 arm was 75.5%, including 22.2% who exhibited a complete response (CR). By contrast, the ORR among 106 patients in the chlorambucil monotherapy group was 30.2%, with no instances of CR.

In stage IB at cutoff time (August 10, 2012), the same patients who took chlorambucil alone were compared with 230 patients who were given rituximab plus chlorambucil. However, the observation times were 6 months longer than in stage IA for the chlorambucil-alone arm and 8 months longer in the rituximab group.

In the rituximab group at cutoff, the ORR was 65.9% among 217 patients, with a CR of 8.3%. By contrast, the response rate for 110 patients who took chlorambucil was 30.0%. In the area of PFS, patients who took the rituximab combination achieved an investigator-assessed median PFS of 15.7 months, versus 10.8 months for chlorambucil alone.

Goede said that results so far indicate that patients in this population would benefit from the addition of either GA101 or rituximab to chlorambucil, and that the potential adverse events (AEs) “can be overcome and do not offset the benefit” of an antibody.

Patients in the GA101 group did experience more AEs than those who took either chlorambucil alone or the rituximab combination. The rates of those exhibiting ≥3 AEs were 66.7% in the GA101 arm, compared with 41.4% in the chlorambucil-alone arm and 46.8% in the rituximab group. Overall, 19.6% of those in the GA101 arm discontinued treatment due to AEs, compared with 14.7% in the chlorambucil-alone group and 13.8% in the rituximab group.

The rates were higher in the GA101 arm compared with chlorambucil-alone and rituximab for neutropenia (34.2% vs 14.7% and 25.3%, respectively) and thrombocytopenia (10.8% vs 3.4% and 3.1%). By contrast, the rates were higher in the chlorambucil-alone group compared with GA101 and rituximab for infection (11.2% vs 6.3% and 8.4%) and anemia (5.2% vs 3.8% and 4.0%).

In addition, AEs leading to death were higher in the chlorambucil-alone arm compared with either GA101 or rituximab (5.2% vs 2.1% or 1.8%), while those leading to a new malignancy were higher among patients who took rituximab than either GA101 or chlorambucil (2.7% vs 2.5% or 0.9%).

Notably, infusion-related reactions (IRRs) were evidenced in 21.3% of those in the GA101 group, compared with no IRRs in the chlorambucil-alone group and 4.0% in the rituximab arm, Goede said. He said IRRs accounted for the higher rate of treatment discontinuation with GA101.

“Virtually all of these IRRs occurred with the first infusion of GA101,” said Goede, adding that there were no subsequent grade 3/4 IRRs and no deaths attributable to a reaction. He said patients who are infused for the first time should be watched but that even if an IRR occurs, he would consider re- administering the drug the next day.

Follow-Up Scans of Limited Value In Detecting DLCBL Relapse

Routine follow-up imaging is of limited value in determining whether patients with diffuse large B-cell lymphoma (DLBCL) have experienced a relapse of their disease, according to findings of a multi-institutional study reported at the 2013 ASCO Annual Meeting. Abstract 8504

DLBCL is the most common form of non-Hodgkin’s lymphoma in adults, with approximately 20,000 new cases diagnosed every year in the United States. Because the disease is potentially curable if it recurs, it can be argued that identifying early relapse is especially important, noted Carrie A. Thompson, MD, a hematologist at the Mayo Clinic in Rochester, Minnesota, and the study’s lead author. She said that the optimal strategy for following patients in remission from DLBCL is not clear, but follow-up has typically included physical exam, laboratory tests, and imaging studies.

Thompson and colleagues at the Mayo Clinic, the University of Iowa, and the Centre Léon Bérard in Lyon, France, looked at post-treatment outcomes, including relapse and death, in 644 newly diagnosed DLBCL patients enrolled in the Molecular Epidemiology Resource project and conducted post-treatment surveillance in 537 patients, 20% of whom (n = 109) experienced relapse of their disease. Sixty-eight percent of patients had symptoms at the time of relapse, 55% had abnormal blood tests, and 42% had an abnormal physical exam finding.

Notably, only eight relapses were detected through a planned surveillance scan before symptoms appeared—equivalent to just 1.5%. Thompson said these findings show that scans add little value for DLBCL patients in remission who had no other symptoms or abnormal findings. Because so many relapses in this study were accompanied by symptoms, she said that patients should be especially vigilant about reporting them. Among the signs of relapse of DLBCL are enlarged lymph nodes, night sweats, unexplained fever, and unintentional weight loss.

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